1. Field of the Invention
The present inventive subject matter relates to novel antibacterial compounds that are capable of inhibiting bacterial multiplication. The present inventive subject matter further relates to methods for treating Gram positive bacterial infections using the inventive compounds.
2. Background
Antibiotics and Antibiotic Resistance. Since their discovery in the 1930's, antibiotics have played a crucial role in the treatment of bacterial infections and diseases. However, with widespread use of broad-spectrum antibiotics, enormous selective pressures are placed on bacterial populations, provoking the evolution of resistance mechanisms and thus resistant bacterial strains. As a result, antibiotics are rendered less useful. In effect, antibiotic resistance results in increased health care costs, and morbidity and mortality from treatment failures.
The glycopeptide antibiotic vancomycin has been a drug of choice against Gram positive bacterial infections for almost thirty years. However, the use of vancomycin is now limited due to the development of resistance, especially notable in multidrug-resistant enterococcal and staphylococcal nosocomial pathogens.
Resistance of Gram positive bacteria to antibiotics is of great concern because of the human infections and diseases they can cause. For instance, Staphylococcus aureus can cause skin lesions, as well as severe infections such as pneumonia, meningitis, and urinary tract infections. Therefore, in the face of diminishing effectiveness of current antibiotics against resistant strains of Gram positive bacteria, a replacement for vancomycin is urgently needed. More generally, there is a continuing need for new and effective antibiotics.
U.S. Pat. No. 4,427,656, issued Jan. 24, 1984 to Cavalleri et al., discloses a chlorine-containing antibiotic substance called antibiotic A/16686 factor A2 in an essentially pure form. The process for the production of antibiotic A/16686 factor A2 by cultivation of an Actinoplanes bacterial strain and the co-produced antibiotic A/16686 factors A1 and A3 are also disclosed. Antibiotic A/16686 factors A1, A2, and A3, as well as the corresponding non-toxic physiologically acceptable acid addition salts are disclosed as antimicrobial agents which are active against gram-positive bacteria.
An improved method for isolating A/16686 is described in U.S. Pat. No. 5,925,550, issued Jul. 20, 1999 to Lancini et al., which discloses a method for selectively enhancing the production of factors A2 and/or A3 of antibiotic A/16686 either to isolate these single components or to enrich the complex in one or both the above components, and which comprises adding an appropriate precursor of the desired antibiotic factor to an A/16686 producing culture during fermentation.
U.S. Pat. No. 5,539,087, issued Jul. 23, 1996 to Restelli et al., discloses a process for recovering the antibiotics produced by the fermentation of an Actinoplanes species or an antibiotic producing mutant thereof, by extraction from a fermentation broth or a process stream.
A use for antibiotics of the ramoplanin group is described in U.S. Pat. No. 5,752,941, issued May 19, 1998 to Romano et al., which discloses central venous polyurethane catheters with a thin hydrophilic coating loaded with an antibiotic of the ramoplanin group, and their use in preventing catheter related infections. These catheters are useful to prevent bacterial adherence and colonization and, therefore, to lower the risk of vascular infections in catheterized patients. The method for preparing the catheter of the invention consists of incubating polyurethane catheters coated with a hydrophilic film in an aqueous solution of the selected antibiotic.
In Boger, D. L., Med. Res. Rev., 21:356–381 (2001) and Jiang, W.; Wanner, J.; Lee, R. J.; Bounaud, P.-Y.; and Boger, D. L., J. Am. Chem. Soc., 124:5288–5290 (2002), a solution-phase total synthesis of the aglycon of ramoplanin A2 and ramoplanose was reported. Three key protected peptide subunits were constructed and sequentially coupled to form a 17-residue linear protected peptide. This intermediate was subsequently cyclized between Phe9 and Orn10 to form the 49-membered macrocycle. This macrocyclization site was chosen to take advantage of the beneficial effects of β-sheet preorganization, as well as previous reports of efficient peptide macrolactamization at a D-amino acid terminus.
At present, there remains a need for new antibiotic substances, especially those which have greater antibacterial activity than current antibiotic compounds and/or reduced adverse side effects. The compounds of the present invention address this need in the art by providing antibiotic activity against both resistant and non-resistant strains of Gram positive bacteria, including vancomycin-resistant Enterococcus faecium and Enterococcus faecalis, and methicillin-resistant Staphylococcus aureus, as well as other bacteria resistant to ampicillin and erythromycin.
This and other features of the invention will be apparent from the detailed description of the inventive subject matter and the claims.